Gopal Thinakaran

Research topics

Matched from this investigator's NIH project titles and abstracts.

• Alzheimer's and Dementia
• Developmental Cognitive Neuroscience
• Learning and Memory

Active NIH awards

• Microglial function of GWAS risk factor BIN1 in Alzheimer's disease pathogenesis and inflammatory signaling

  4R01AG079141-02

  NIA · FY 2025 · $709K

  PROJECT SUMMARY BIN1, an adaptor protein encoded by the second most common susceptibility GWAS risk factor of late-onset AD, regulates membrane dynamics in the context of endocytosis, membrane remodeling, and synaptic vesicle release. Large-scale expression datasets have reported high-level BIN1 expression in microglia, and AD- associated BIN1 SNPs are thought to alter BIN1 expression through a microglia-specific enhancer. However, the precise functional role(s) of microglial BIN1 in regulating AD pathophysiology has not been investigated systematically. Our central hypothesis is that microglial BIN1 plays an essential role in neuroinflammatory signaling through which BIN1 influences AD pathophysiology. Our preliminary studies show that the loss of Bin1 expression in vitro (cultured microglia) and in vivo (microglia-specific cKO mice) profoundly impairs proinflammatory gene expression and the upregulation of several disease-associated microglia (DAM) genes. Our transcriptomic profiling identified BIN1 as a homeostatic microglial regulator with a non-redundant role in activating proinflammatory response upstream of Apoe, Trem2, and Tyrobp, and upstream of PU.1 and IRF1. BIN1 was predicted to regulate type 1 and 2 interferon responses in microglia in vitro and in vivo. Collectively, these findings offer important insights into microglial BIN1 function, demonstrating its significance in brain inflammatory response. The overall objective of this proposal is to explore BIN1’s role in microglia further, especially in the context of AD pathogenesis, and gain molecular insights. The goal of Aim 1 is to generate 5XFAD:Bin1 cKO mice to elucidate microglial BIN1 function in the modulation of cerebral amyloid burden and amyloid-associated pathophysiology. We will conduct detailed biochemical, molecular, and neuropathological characterization and perform transcriptomics profiling of neuroinflammation and DAM transition to understand BIN1’s role in microglial response to amyloid pathology. Aim 2 studies seek to generate PS19:Bin1 cKO mice to elucidate the involvement of microglial BIN1 function in tau pathophysiology and pathology propagation using detailed neuropathology and comprehensive biochemical, proteomics, and molecular analyses. Aim 3 studies will investigate the mechanistic role of BIN1 as a crucial regulator of early inflammatory signaling events in microglia. We will use unbiased and hypothesis-driven approaches to define the microglial BIN1 interactome and elucidate how BIN1 and its binding partners are reorganized in a context-dependent manner to facilitate immune signaling via key microglial receptors. This timely and unique proposal is highly innovative. Our strategy to use microglia-specific inducible Bin1 cKO mice represents the most direct in vivo approach to rigorously investigate how microglial BIN1 regulates AD pathophysiology and gain insights using comprehensive transcriptomics, proteomics, and interactome characterization. We believe that the successful completion of the proposed research will fill significant gaps in our understanding of BIN1 as a risk factor for LOAD and guide future functional characterizations of molecular pathways and pathogenic mechanisms regulated by this major LOAD risk gene.

• The role of Alzheimer's disease GWAS risk factor BIN1 in tau neuropathology and propagation in vivo

  4R01AG077610-02

  NIA · FY 2025 · $687K

  BIN1, the most significant late-onset Alzheimer’s disease (LOAD) susceptibility locus identified via GWAS, encodes an adaptor protein that regulates membrane dynamics in the context of endocytosis and neurotransmitter vesicle release. BIN1 can directly bind to tau, leading to the suggestion that BIN1 might influence AD tangle pathology. However, we and others have failed to find evidence directly linking cytosolic BIN1·tau interaction to AD risk. In contrast, compelling in vitro evidence suggests that BIN1’s function in membrane dynamics limits pathogenic tau seed uptake and influences tau release. This indicates that neuronal BIN1 might regulate tau pathology propagation. In vivo evidence to support this notion is still lacking. In order to elucidate how BIN1 function relates to disease risk for AD, it is imperative to better understand BIN1’s role in tau pathogenesis and disease progression using appropriate animal models. Our preliminary characterization of tau pathogenesis in Bin1-cKO mice reveals a complex picture: the loss of BIN1 expression in tau transgenic mice exacerbated tau pathology in the spinal cord, accelerated disease progression, and caused early death. Intriguingly, BIN1 loss also attenuated brain atrophy and protected the hippocampus from neuroinflammation, synapse, and neuronal loss, thus, profoundly reducing tau neuropathology in select regions. These intriguing findings need to be extended because of their direct clinical implications. Our central hypothesis is that BIN1 exerts its function as a risk factor by modulating tau pathophysiology in a region-specific manner. Since BIN1 is a potential target for future therapies, the overall objective of this investigation is to characterize BIN1 modulation of tau neuropathology in vivo and gain molecular insights into region-specific BIN1 functions. The goal of Aim 1 is to generate cell-type-specific inducible Bin1-cKO using CamK- and PLP-CreERT-drivers, characterize tau pathogenesis using in vivo longitudinal MR imaging and detailed neuropathology and test the hypothesis that BIN1 expression modulates tau neuropathology in select brain regions. Aim 2 studies will apply complementary stereotaxic injection approaches to directly test the hypothesis that BIN1 exerts a region-specific influence on neuron-to-neuron tau spread or influences uptake and pathology propagation via mutant tau template interaction. Aim 3 studies will perform molecular analyses through bulk and digital spatial transcriptomic strategies to map cell-autonomous and non-cell-autonomous disease-related gene expression changes and elucidate functional pathways involved in BIN1-mediated region-specific pathology modulation. This timely and unique proposal is highly innovative. This investigation using multiple Bin1-cKO mice represents the most direct in vivo approach to rigorously investigate BIN1’s involvement in the biological pathways of tau neuropathology. We believe that the successful completion of the proposed investigation will fill significant gaps in our understanding of BIN1 as a risk factor for LOAD and guide future functional characterizations of molecular pathways and pathogenic mechanisms regulated by this major LOAD risk gene.